Time Course and Potentiation of Fluoxetin Action

氟西汀作用的时间进程和增强作用

基本信息

批准号：
6692989
负责人：
GEORGE BATTAGLIA
金额：
$ 3.94万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-01-14 至 2005-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant) The long-term goal of the proposed studies is to provide novel therapeutic approaches for the treatment of mood disorders that will work more rapidly and more effectively than the currently available medications. The introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) has revolutionized psychiatry. In addition to their effectiveness in the treatment of depression, SSRIs also have proven effective for the treatment of several mood disorders for which the older medications were ineffective. These disorders include anxiety, obsessive compulsive disorder, aggression, eating disorders and premenstrual syndrome. However, a lag time of about 2-3 weeks exists from the onset of medication until the first signs of improvement appear. This delayed onset of therapeutic effects is a severe problem. Some of the suicides of depressed patients occur during this lag time. Therefore, there is a great need to find therapeutic approaches that will work more rapidly. Studies supporting the parent grant indicate that treatment with SSRIs produces a delayed-onset, homologous desensitization of post-synaptic serotoninlA( 5-HT1A) receptors in the hypothalamus. This desensitization is most likely mediated by increased levels of 5-HT in the synapse and the resulting over-activation of post-synaptic receptors. Studies in depressed patients indicate that the therapeutic effectiveness of SSRIs is dependent on maintaining high levels of 5-HT in the synaptic cleft. The 5-HT reuptake mechanism is the primary mechanism terminating the activation of post-synaptic receptors by 5-HT in the synaptic cleft. However, the release of 5-HT from the nerve terminals is highly regulated by inhibitory 5-HT1A autoreceptors on the soma and dendrites of the serotonergic cells in the raphe nuclei and by inhibitory 5-HT1B/1D autoreceptors on the serotonergic nerve terminals in forebrain regions. Thus, the overall hypothesis is that during SSRI therapy, the inhibitory influences of 5-HT autoreceptors must be overcome to allow SSRIs to increase the levels of 5-HT in the synaptic cleft. The proposed studies will use in vivo microdialysis approaches to investigate the time courses of changes in both 5-HT1A and 5-HT1B/1D autoreceptors, and thus determine whether these receptors contribute to the delay in onset of fluoxetine-induced increase in extracellular levels of 5-HT in several forebrain regions. In addition, the studies will investigate whether combining fluoxetine with selective 5-HT1A and/or 5-HT1B/1D antagonists will accelerate the fluoxetine-induced increase in extracellular levels of 5-HT. The results of the present studies will provide the scientific foundation for the use of specific autoreceptor antagonists as adjunctive therapy with SSRIs to produce a more rapid and effective therapy of mood disorders.

描述（由申请人提供）拟议研究的长期目标是提供新的治疗方法治疗情绪障碍的方法将更迅速地发挥作用比目前可用的药物更有效。介绍选择性血清素再摄取抑制剂（SSRIs），例如氟西汀（百忧解）彻底改变了精神病学。除了其治疗效果外除了抑郁症之外，SSRIs 也被证明对治疗多种抑郁症有效旧药物对情绪障碍无效。这些疾病包括焦虑、强迫症、攻击性、饮食疾病和经前综合症。但有大约2-3周的滞后时间从开始用药到出现第一个改善迹象为止出现。这种治疗效果的延迟出现是一个严重的问题。一些抑郁症患者的自杀就发生在这段滞后时间内。因此，有非常需要找到能够更快起效的治疗方法。支持家长资助的研究表明，使用 SSRIs 治疗会产生突触后血清素lA的延迟发生、同源脱敏（ 5-HT1A) 下丘脑受体。这种脱敏最有可能是由突触中 5-HT 水平增加介导，并由此产生突触后受体的过度激活。对抑郁症患者的研究表明 SSRIs 的治疗效果取决于突触间隙中维持高水平的 5-HT。 5-HT再摄取机制是终止突触后激活的主要机制突触间隙中的 5-HT 受体。然而，5-HT 的释放神经末梢受到抑制性 5-HT1A 自身受体的高度调节中缝核中血清素能细胞的体细胞和树突血清素能神经末梢上的抑制性 5-HT1B/1D 自身受体前脑区域。因此，总体假设是，在 SSRI 治疗期间，必须克服 5-HT 自身受体的抑制影响才能允许 SSRIs 增加突触间隙中 5-HT 的水平。拟议的研究将使用体内微透析方法研究变化的时间过程在 5-HT1A 和 5-HT1B/1D 自身受体中，从而确定这些是否受体有助于延迟氟西汀诱导的增加的发作几个前脑区域的细胞外 5-HT 水平。此外，研究将调查氟西汀是否与选择性 5-HT1A 结合使用和/或 5-HT1B/1D 拮抗剂会加速氟西汀诱导的细胞外 5-HT 水平。目前的研究结果将提供使用特定自身受体拮抗剂作为药物的科学基础 SSRIs 的辅助治疗可产生更快速、更有效的治疗情绪障碍。